Hindawi

BioMed Research International

Volume 2019, Article ID 8142368, 17 pages
https://doi.org/10.1155/2019/8142368

Review Article
Biologics in the Treatment of Lupus Erythematosus:
A Critical Literature Review

Dominik Samotij and Adam Reich

Department of Dermatology, University of Rzeszow, ul. Fryderyka Szopena 2, 35-055 Rzeszow, Poland

Correspondence should be addressed to Adam Reich; adi medicalis@go2.pl

Received 7 May 2019; Accepted 18 June 2019; Published 18 July 2019

Academic Editor: Nobuo Kanazawa

Copyright © 2019 Dominik Samotij and Adam Reich. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease affecting multiple organ systems that runs
an unpredictable course and may present with a wide variety of clinical manifestations. Advances in treatment over the last
decades, such as use of corticosteroids and conventional immunosuppressive drugs, have improved life expectancy of SLE sufferers.
Unfortunately, in many cases effective management of SLE is still related to severe drug-induced toxicity and contributes to organ
function deterioration and infective complications, particularly among patients with refractory disease and/or lupus nephritis.
Consequently, there is an unmet need for drugs with a better efficacy and safety profile. A range of different biologic agents have been
proposed and subjected to clinical trials, particularly dedicated to this subset of patients whose disease is inadequately controlled
by conventional treatment regimes. Unfortunately, most of these trials have given unsatisfactory results, with belimumab being the
only targeted therapy approved for the treatment of SLE so far. Despite these pitfalls, several novel biologic agents targeting B cells,
T cells, or cytokines are constantly being evaluated in clinical trials. It seems that they may enhance the therapeutic efficacy when
combined with standard therapies. These efforts raise the hope that novel drugs for patients with refractory SLE may be available
in the near future. This article reviews the current biological therapies being tested in the treatment of SLE.

1. Introduction 2. B Cell-Targeted Therapies

Systemic lupus erythematosus (SLE) is a chronic multi-
systemic inflammatory disease, in which tissue injury is a
consequence of immune dysregulation and tolerance loss
to nuclear self-antigens. Conventional treatment modalities
for SLE have allowed an improvement of survival; however,
their use is associated with a significant risk of toxicity
and a wide range of morbidities. The research conducted in
recent years has significantly contributed to the extension
of our knowledge on SLE immunopathology and provided
important data on the potential targets of novel therapies
(Figure 1). Efforts are being constantly made to develop drugs
with a more selective mode of action, targeting the strictly
defined immunological targets relevant to SLE, while at the
same time allowing the reduction of adverse events (AEs) of
the previously used drugs. In this review we summarized the
available results of clinical trials with selected biological drugs
in SLE (Table 1).
Increased activity of B cells has been demonstrated both
in animal models and in human with SLE [1, 2]. SLE is
characterized by abnormal activation and differentiation of B
cells as well as defective elimination of autoreactive B cells [3].
Increased B cell activity results in polyclonal hypergamma-
globulinemia and the production of numerous autoantibod-
ies, in particular those recognizing insoluble (e.g., histones
or native DNA) and soluble (extractable) nuclear antigens
(ENA, e.g., Smith or snRNP antigen) [4]. The importance of
B cells in SLE physiopathology is related not only to their
ability to produce autoantibodies, but also to the capability
of presenting autoantigens to T cells through the BCR (B cell
receptor) and cytokine secretion and modulation of dendritic
cell (DC) activity [5, 6]. An ideal B cell-targeted drug
should therefore eliminate pathogenic B cells and/or trigger
B cell expansion and promote the function of protective
cells.
 2

Table 1: Biologics in systemic lupus erythematosus.

Clinical phase of
Clinical phase of
Agent Mechanism of action Molecular target completed clinical Major outcomes/Safety profile Future prospects
ongoing clinical trials
trials
++
(approved in EU
Significantly higher SRI-4 response at week 52 in three and US as for
Belimumab BLyS inhibition BLyS (soluble) III [19, 20, 27] III, IV major phase III clinical trials than placebo. Positive the use in
impact on immunological parameters. non-renal SLE
as add-on
therapy)
No significant benefits over placebo (SRI-5). Slightly +/-
BLyS/APRIL BLyS (soluble and
Tabalumab III [38, 39] - higher proportion of responders compared to placebo (studies were
inhibition membrane-bound)
in post hoc analysis using SRI-4. discontinued)
Blisibimod BLyS/APRIL BLyS (soluble and No significant clinical benefits. Beneficial biological
III [43] - +/-
inhibition membrane-bound) effects.
Slightly better SRI-4 response in patients with
BLyS/APRIL
Atacicept BLyS, APRIL IIb [49] - low-to-moderate disease activity compared to placebo. +/-
inhibition
High risk of infective complications.
Anti-dsDNA
Abetimus antibody-producing B
B cell tolerance Promising results in phase II/III clinical trials. No
sodium cells/circulating II/II, III [53, 54] - +/-
induction efficacy in phase III clinical trials.
anti-dsDNA
antibodies
Primary end points in clinical trials not reached. Large
Rituximab II, III
B cell depletion CD20 III [62, 63] number of reports and recommendations confirming +
(including LN)
its efficacy in certain subsets of patients.
Ocrelizumab Clinical trials prematurely terminated due to increased
B cell depletion CD20 III [85] - -
risk of adverse events.
Ofatumumab Reduction of disease activity and anti-dsDNA antibody
B cell depletion CD20 Case series [87, 88] - +
titres. Normalization of C3 complement component.
Obinutuzumab Preclinical studies B cell depletion at least 2-fold more efficient than
B cell depletion CD20 II (LN) +
[93] rituximab.
BioMed Research International
 Table 1: Continued.
Clinical phase of
BioMed Research International

Clinical phase of
Agent Mechanism of action Molecular target completed clinical Major outcomes/Safety profile Future prospects
ongoing clinical trials
trials
Epratuzumab B cell signaling
CD22 III [102] - Lack of clinical efficacy. Favorable safety profile. -
modulation
Rontalizumab Type I interferon No general superiority over placebo. Significant benefit
IFN𝛼 II [119] - +/-
inhibition in low IFN signature group.
+
Type I interferon
Sifalimumab IFN𝛼 IIb [122] - Better SRI-4 response in high IFN signature group. (studies were
inhibition
discontinued)
Anifrolumab Type I interferon III (several trials
IFNAR1 IIb [126] Better SRI-4 response in high IFN signature group. +
inhibition including LN)
Tocilizumab Improvement in clinical parameters. Reduction of
Cytokine inhibition IL-6 receptor I [140] - +
anti-dsDNA antibody titers.
Sirukumab II (proof-of-concept) Lack of clinical efficacy. Frequent serious adverse
Cytokine inhibition IL-6 - -
[142] events.
Monoclonal antibody
Eculizumab Complement Short-lasting biological efficacy was noted only for
against complement I [149] - -
blockade higher doses.
component C5
Ruplizumab/ T cell costimulation Open label/ Clinical trials were terminated due to thromboembolic
CD40L - -
Toralizumab blockade I [151, 152] complications.
Dapirolizumab T cell costimulation
CD40-CD40L Ib [153] III Disease activity reduction (SRI-4, BICLA). +
blockade
No significant clinical benefits. Most beneficial in
Abatacept T cell costimulation CD28/CTLA4-
IIb, II/III [159, 160] III (including LN) patients who had polyarthritis as the primary +
blockade CD80/CD86
manifestation. Safe and well tolerated.
APRIL: a proliferation-inducing ligand; BICLA: BILAG-based Combined Lupus Assessment; BLyS: B lymphocyte stimulator; CD40L: CD40 ligand; CTLA4: cytotoxic T lymphocyte associated protein 4; IFN𝛼:
interferon alpha; IFNAR1: interferon alpha receptor 1; IL-2: interleukin 2; IL-6: interleukin 6; LN: lupus nephritis; SLE: systemic lupus erythematosus; SRI-4: Systemic Lupus Erythematosus Responder Index 4.
3
4 BioMed Research International

anifrolumab
rontalizumab mDC
sifalimumab rituximab/obinutuzumab
IFN
CD80/86
pDC epratuzumab
abatacept

CTLA4
belimumab
CD20
CD22
tabalumab BAFF BAFF-R
/blisibimod T cell
B cell
mbBAFF CD40
BCMA CD40L

dapirolizumab
TACI ruplizumab/toralizumab
atacicept
IL6-R IL6-R
APRIL

mDC tocilizumab

Figure 1: Targets for biological therapies in systemic lupus erythematosus (modified from [14]). APRIL: a proliferation-inducing ligand;
BAFF: B cell-activating factor belonging to the TNF family; BAFF-R: BAFF receptor; BCMA: B cell maturation antigen; CD40L: CD40
ligand; CTLA4: cytotoxic T lymphocyte associated protein 4; IFN𝛼: interferon alpha; IL6-R: interleukin 6 receptor; mbBAFF: membrane-
bound BAFF; mDC: myeloid dendritic cell; pDC: plasmacytoid dendritic cell; TACI: transmembrane activator-1 and calcium modulator and
cyclophilin ligand interactor.

The protein called BLyS (B lymphocyte stimulator), also
known as BAFF (B cell-activating factor belonging to the
tumor necrosis factor family) or TNFSF13B (the tumor necro-
sis factor ligand superfamily member 13B), belongs to the
superfamily of TNF ligands [7, 8]. BLyS is a soluble membrane
protein that is secreted by monocytes, neutrophils, and T cells
and DCs [9]. BLyS binds only to the receptors located on the
surface of B cells. The following 3 types of receptors for BLyS
were identified: BR3 (BLyS receptor 3), TACI (transmem-
brane activator-1 and calcium modulator and cyclophilin
ligand interactor), and BCMA (B cell maturation antigen).
BR3 binds only BLyS whereas TACI and BCMA may also
bind APRIL (a proliferation-inducing ligand). BLyS binds
with much higher affinity to BR3 than to BCMA, whereas
APRIL has a greater affinity for BCMA and little or no binding
capacity for BR3. Biological activity of BLyS thus depends
to the greatest extent on BR3 [10]. BLyS plays an important
role in the differentiation, activity, and survival of B cells
[11]. Increased concentration of BLyS affects the survival
of B cells that produce autoantibodies by inhibiting their
apoptosis [12]. BLyS-targeted therapy selectively reduced the
number of CD20+ lymphocytes and short-lived plasma cells
as well as anti-double-stranded DNA (anti-dsDNA) antibody
titers in patients with SLE; however, this therapy did not
affect memory B cells and long-lived plasma cells [13]. The
discovery of the crucial role of BLyS in the pathogenesis
of SLE, as a cytokine responsible for survival, activation,
and differentiation of B cells, has led to the development
of new molecules directed against BAFF, which have been
demonstrated to be promising agents in clinical trials.
2.1. B Cell Growth and Survival Factors Inhibitors
2.1.1. Belimumab. Belimumab is the first drug to be registered
for the treatment of SLE since 1955, when hydroxychloro-
quine was repurposed and approved [15]. Belimumab in
intravenous (IV) formulation administered at a dose of 10
mg/kg body weight (BW) on days 0, 14, and 28 and then every
28 days was approved by the Food and Drug Administration
(FDA), the European Medicines Agency (EMA), and the
National Institute for Health and Clinical Excellence (NICE)
[16, 17]. Belimumab is indicated for the treatment of adult
patients with seropositive SLE with active cutaneous or joint
disease, who do not respond to standard treatment, excluding
patients with lupus nephritis (LN) and severe central nervous
system (CNS) involvement [18].
Belimumab is a human IgG1𝜆 monoclonal antibody
that has the ability to bind the soluble BLyS receptor pre-
venting survival of B cells; it further reduces the differ-
entiation of B lymphocytes into plasma cells that produce
immunoglobulins (Igs). BAFF-neutralizing therapy with beli-
mumab reached the primary end points in two large phase III
clinical trials conducted on over 1,600 SLE patients [19, 20].
The results of these studies were the basis for the registration
BioMed Research International
of this drug by the FDA. Post hoc analyses of these trials
suggested a significant benefit from belimumab treatment,
especially in patients with more active disease, treated with
higher doses of corticosteroids (CS), with the presence of
anti-dsDNA antibodies and low serum levels of C3 and C4
complement components [21]. The initial favorable observa-
tions on the use of belimumab in SLE had already been made
based on phase I studies and they were confirmed in the
subsequent trials [22]. A total of 449 patients included in the
second phase study received the drug at a dose of 1, 4, and
10 mg/kg BW or placebo as an addition to standard therapy
on days 0, 14, and 28 and then every 28 days for 52 weeks. A
serologically active group (71.5% of patients with detectable
antinuclear or anti-dsDNA antibodies) was isolated from the
patients studied. In these individuals, a statistically significant
decrease in the SELENA-SLEDAI (Safety of Estrogens in
Lupus Erythematosus National Assessment-Systemic Lupus
Erythematosus Disease Activity Index) score, a reduction in
PGA (Physician Global Assessment) score, and improvement
of the quality of life (QoL) were found. The study also showed
that belimumab caused depletion of about 60-70% of CD20+
cells and decreased the number of naı̈ve and activated B cells
and plasmacytoid cells. Reduction of anti-dsDNA antibody
titres by 29% and reduction of the total Ig levels were also
observed. At the same time, a favorable safety profile was
demonstrated as the number of AEs (including serious AEs
and infections) in patients receiving the drug was similar to
the number of AEs in the placebo group [23].
Phase III clinical trials (BLISS-52 and BLISS-76) were
carried out according to a similar protocol, but they were
undertaken in different geographical regions. Patients with
serologically positive SLE were randomized to one of three
groups: the placebo group and the belimumab group at a
dose of 1 mg/kg BW or at a dose of 10 mg/kg BW. The
drug was administered on days 0, 14, and 28 and then
every 28 days. In both studies, the primary end point,
i.e., the proportion of patients achieving SRI-4 (Systemic
Lupus Erythematosus Responder Index 4), was significantly
higher among those receiving belimumab at a dose of 10
mg/kg BW than placebo (58% vs. 44% in BLISS-52 and
43% vs. 34% in BLISS-76). A significantly higher proportion
of patients treated with belimumab exhibited an improve-
ment in musculoskeletal and mucocutaneous symptoms [24].
There was also a positive effect of the drug on immunological
indicators of disease activity (reduction of Ig concentra-
tion and increase in complement components, reduction
of autoantibody production), as well as improvement of
QoL and level of fatigue [25, 26]. In the BLISS-52 study, a
significantly higher number of patients in the 10 mg/kg BW
arm were eligible for prednisone dose tapering by 50% in
weeks 24-52 compared to those receiving placebo, although
such a prominent CS-sparing effect was not observed in
the BLISS-76 study. In addition, a study using belimumab
given as a subcutaneous (SC) injection of 200 mg every 7
days (BLISS-SC study) combined with standard treatment
regimen in patients with disease activity score ≥8 points
according to SELENA-SLEDAI showed SRI-4 response at
week 52 to be significantly higher in the active group than
in the placebo group (65% and 47%, respectively). Moreover,
5
patients treated with belimumab had a 62% lower risk of
severe exacerbation compared to the placebo group [27].
A recent network meta-analysis comparing the efficacy and
safety of belimumab administered as an IV or SC injection
has demonstrated that IV belimumab at a dose of 10 mg/kg
BW and SC belimumab 200 mg had the highest probability,
based on surface under the cumulative ranking curve, of
being the best treatment for achieving the SRI response
at week 52. Furthermore, it was concluded that both of
aforementioned belimumab dosage regimens combined with
standard therapy were efficacious interventions for active SLE
and were not associated with a significant risk of SAEs [28].
Despite relatively high costs of therapy, pharmacoeconomic
studies carried out in Greece, Spain, and Italy have shown that
belimumab treatment is profitable [29–32]. The European
expert panel guidelines published in 2017 recommended the
use of belimumab in treatment-resistant and CS-dependent
SLE, in the absence of renal and CNS involvement or severe
autoimmune thrombocytopenia [33]. A frequent indication
for adding belimumab to the standard treatment is also the
constant progression of immunological markers of disease
activity [34]. Experts suggest that the efficacy of the drug
should be evaluated 16 weeks after the first drug administra-
tion at the earliest. Lack of efficacy after 6 months of treatment
is an indication for the drug discontinuation [35].
2.1.2. Tabalumab. Tabalumab is a fully human IgG4 mon-
oclonal antibody that neutralizes BAFF (both soluble and
membrane-bound forms) but does not bind to APRIL [36,
37]. This biologic was directly studied in two 52-week phase
III randomized double-blind placebo-controlled clinical tri-
als in patients with active SLE, but without severe renal
involvement and neuropsychiatric symptoms [38, 39]. The
first study (ILLUMINATE-1) included 1,164 patients with
moderate-to-severe SLE (SELENA-SLEDAI score ≥6 points).
At week 52, the proportion of patients who achieved the
primary end point (SRI-5) was not significantly higher among
those receiving the drug than among those on placebo.
Secondary end points (including time to the first severe
flare of the disease, CS-sparing effect, and reduction of
fatigue level) were also not met. Nonetheless, tabalumab
significantly affected the immunological parameters of the
disease; marked reductions in the serum concentration of
anti-dsDNA antibodies, an increase in serum levels of the
C3/C4 complement components, and a reduction in the
total B cell count, Ig concentration, and BAFF levels were
observed. The frequency of AEs and mortality did not differ
between those treated and those receiving placebo.
The second study (ILLUMINATE-2) concerned patients
with active SLE (n = 1,124). The primary end point (per-
centage of patients who achieved SRI-5) was met at week
52 in the 120 mg group every 2 weeks (38% vs. 28% in the
treatment group and placebo, respectively; p = 0.002). On
the other hand, no secondary end points have been met. In
post hoc analyses of the efficacy of tabalumab using the same
clinical response rate that was used in the belimumab phase
III trials (i.e., SRI-4 instead of SRI-5), a statistically significant
11% difference in the response rate in favor of the group of
patients on tabalumab was observed compared to placebo
6 BioMed Research International
receivers [40]. Nevertheless, further work on tabalumab has
been halted.
2.1.3. Blisibimod. Blisibimod is a fusion protein composed of
four BAFF-binding domains fused to the N-terminal Fc frag-
ment of human IgG1 Ig. This biologic agent is a potent BAFF
inhibitor administered in the form of SC injections [41]. In
a double-blind, randomized, placebo-controlled clinical trial
(PEARL-SC), 547 patients with serologically active SLE and
SELENA-SLEDAI score ≥6 points were randomized to 3 dif-
ferent doses of blisibimod or placebo. At week 24, the highest
dose group (200 mg once weekly) had a significantly higher
SRI-5 response rate than the placebo group. Blisibimod
treatment was associated with a significant improvement in
biomarkers: lowering of anti-dsDNA antibodies, increase in
serum C3/C4 concentrations, and reduction of B cell number.
The drug was well tolerated in all doses [42].
The results of a multicenter, placebo-controlled, phase III
randomized, double-blind study (CHABLIS-SC1) conducted
on a group of 442 seropositive SLE patients with persistent
high disease activity (SELENA-SLEDAI ≥10 points) despite
use of CS and other standard treatments did not show
significant differences in the frequency of the primary end
point of the study (SRI-6) between blisibimod and placebo
receivers (47% vs. 42%, respectively). The secondary end
points (SRI-4 and SRI-8) were also not reached. Despite
disappointing results in terms of study end point measures,
significant beneficial changes in the number of B cells, the
concentration of Igs, and complement components were
demonstrated similarly to the phase IIb clinical trial [43].
The continuation of CHABLIS-SC1 was CHABLIS7.5
study (also known as CHABLIS-SC2), allowing the recruit-
ment of patients with renal involvement, which included
patients with severe SLE (SELENA-SLEDAI score ≥10 points),
the presence of anti-dsDNA antibodies in serum and
depressed levels of complement components despite the
use of CS in a dose compatible with the standard-of-care.
However, this study was terminated prematurely [44].
2.1.4. Atacicept. Atacicept (TACI-Ig) is a fully human recom-
binant fusion protein that neutralizes both BAFF and APRIL
[45]. This agent is an inhibitor of both soluble and membrane-
associated BAFF. Placebo-controlled phase Ib clinical trial
with dose escalation in patients with SLE showed the bio-
logical efficacy of atacicept as measured by reduction in
peripheral B cell counts and dose-related Ig levels [46].
Subsequently, a 52-week phase II/III study with atacicept (150
mg SC 2x weekly for 4 weeks, then 1x weekly), double-blind,
randomized, placebo-controlled in patients with active LN
who received an additional high dose of CS and mycophe-
nolate mofetil (MMF) (3g/day) was set up. Unfortunately,
this trial was discontinued shortly after initiation due to an
unexpected severe decrease of serum IgG levels and serious
infections [47].
Another double-blind phase II/III trial, with randomiza-
tion and placebo control, was performed on a group of 461
patients. Participants of this study with active SLE according
to the BILAG (British Isles Lupus Assessment Group) index
(≥1 item in the BILAG A and/or B domain), previously
treated with CS with gradual dose reduction for 10 weeks
who reached the BILAG C or D domain, were randomized
in a 1:1:1 ratio to placebo and two doses of atacicept (75 mg
or 150 mg 2x per week for 4 weeks, then 1x per week for
48 weeks). The primary end point, defined as a significantly
decreased proportion of patients who developed a new flare
from BILAG A or BILAG B domain scores, was not met in
the 75 mg arm; time to exacerbation was also not significantly
prolonged between the 75 mg treatment arm and the placebo
arm. Treatment of patients in the 150 mg arm was not further
continued due to serious AEs. Administration of the drug
in both doses resulted in an improvement with respect to
the immunological parameters of the disease, as well as a
reduction of the total Ig concentrations [48]. Opposingly,
the results of the 24-week phase IIb randomized placebo-
controlled trial (ADDRESS II) for patients with active SLE
(SLEDAI-2K score ≥6 points) receiving standard therapy
completed in 2016 did not confirm the higher incidence of
serious AEs with both doses of atacicept (75 mg and 150
mg SC) compared to placebo. The percentage of treatment
responses expressed by SRI-4 was higher among patients
receiving the drug than placebo. Interestingly, patients with
high baseline disease activity (SLEDAI-2K score ≥10 points)
did not benefit from the therapy [49].
Post hoc analysis showed a relationship between the dose
administered and the reduction of Ig concentrations and
the frequency of exacerbations. According to the original
hypothesis, elevated BLyS and APRIL levels were associated
with better response, which was expressed primarily by a
more pronounced decrease in the frequency of flares [50].
2.2. Immunological Tolerance-Inducing Agents (Tolerogens)
2.2.1. Abetimus. Abetimus (abetimus sodium or LJP-394)
is a synthetic molecule consisting of deoxynucleotide-like
molecules in a tetrameric form, mimicking the dsDNA-
containing immune complexes. It has the ability to bind the
Ig receptor to native DNA on the surface of B cells by cross-
reacting, which affects intracellular transmission leading to
anergy or apoptosis of these cells. This further induces B
cell tolerance to own antigens derived from native DNA
(the so-called tolerogenic therapy) [51]. Abetimus is a highly
specific molecule consisting of over 97% of native DNA;
hence it interacts only with molecules that recognize native
DNA. The action of abetimus in reducing the concentration
of circulating anti-dsDNA antibodies persists long after
its administration, even when it is already absent in the
circulation [52].
Despite drug efficacy having been demonstrated in a
randomized, double-blind, placebo-controlled phase II/III
trial in LN individuals (reduction of exacerbation frequency
and prolongation of time to the first flare), a phase III study
in patients with anti-dsDNA-positive SLE did not confirm its
effectiveness with respect to reduction of the frequency of
SLE flares, even in a subgroup of patients with high-affinity
antibodies to the DNA epitope found in abetimus [53, 54].
Despite that, this drug reduced the concentration of anti-
dsDNA antibodies, caused an increase in serum C3 comple-
ment component, and was well tolerated. Shortly thereafter,
BioMed Research International
a large number of patients (n = 943) were included in the
subsequent randomized, double-blind, placebo-controlled
phase III clinical trial (ASPEN) employing a higher dose of
drug with a high risk of LN flare. This study, however, was
prematurely interrupted based on a preliminary analysis that
did not show any benefits of using this molecule [55].
2.3. Monoclonal Antibodies Targeting B Cell Surface Antigens
2.3.1. Anti-CD20 Monoclonal Antibodies
(1) Rituximab. Rituximab (RTX) is a chimeric mouse-human
monoclonal antibody that selectively binds to the CD20
transmembrane antigen present on the surface of B cells
(from pre-B cells to memory B cells). RTX selectively binds
CD20-positive cells which results in cell-cycle arrest and
eventually leads to apoptosis. These cells are further destroyed
via complement-dependent lysis, antibody-dependent cellu-
lar cytotoxicity, and phagocytosis; these mechanisms depend
on the Fc portion of the antibody binding to Fc𝛾Rs on
immune cells [56]. B cell dysfunction causes disruption of
their differentiation towards plasma cells and, as a conse-
quence, a reduction in the production of pathogenic autoan-
tibodies: anti-dsDNA and anti-nucleosome antibodies. Inhi-
bition of CD20-positive cells induces depletion of all mature
B cell forms but has no effect on plasma cells. Repopulation of
B cells, which usually occurs 6-9 months after administration
of RTX, predominantly involves a subset of naı̈ve or antigeni-
cally inexperienced transitional B cells [57]. Repeated RTX
administrations may cause hypogammaglobulinemia [58].
The first reports on the effectiveness of RTX in patients
with SLE come from 2002 [59]. In subsequent studies, the
efficacy of this drug was confirmed in patients with SLE
and LN, with joint and mucocutaneous symptoms, serositis,
cytopenia, and neurological involvement [60]. Analysis of 188
cases of RTX use in SLE in small, uncontrolled studies con-
firmed its effectiveness in this indication [61]. However, two
large-scale, double-blind, randomized, placebo-controlled
studies in patients with nonrenal SLE (EXPLORER, phase
II/III) and LN (LUNAR, phase III) failed to meet their major
end points [62, 63].
The first trial included 257 patients with moderate-to-
high activity extrarenal disease (defined as BILAG A in
≥1 domain or BILAG B in ≥2 domains) persisting despite
treatment with one immunosuppressive drug [62]. Notably, it
was later emphasized that major clinical end point of this trial
defined as achieving BILAG C scores or better in all assessed
organs is difficult to obtain in “real life” setting [64].
The second clinical trial evaluated the efficacy of RTX
in patients with active LN. In addition to RTX, the patients
received CS and MMF (at a dose of 2 g/day). At week 52, no
statistically significant differences were found in the number
of patients achieving primary and secondary end points
between RTX and placebo arms. However, the percentage
of responders in the RTX arm was higher compared to
placebo (57% vs. 46%). Greater improvement with respect
to SLE-specific immunological markers, such as the concen-
tration of anti-dsDNA antibodies and C3/C4 complement
component levels, was also observed in the group of patients
7
who received RTX. Neutropenia, leukopenia, herpes zoster,
and opportunistic infections, as well as hypotension, fever,
skin rash, and other AEs directly related to the IV infu-
sion, were quantitatively more frequent in the RTX group
[63]. Seeking explanations for the disappointing results of
the LUNAR study, it is often underlined that background
immunosuppressive regimen with repetitive infusion of 1 g
methylprednisolone and high-dose oral MMF (as required by
the protocol) could mask the effectiveness of RTX [65].
The results of the clinical trials discussed above did
not show any significant benefits of using RTX in patients
with SLE and somewhat diminished its importance in the
treatment of this disease. Nevertheless, its frequent off-label
use in daily clinical practice to control treatment-resistant
SLE symptoms (including LN) should not be overlooked
[66–70]. In patients with LN, RTX has been often given
in combination with CS and/or other immunosuppressants,
such as cyclophosphamide (CY), MMF, azathioprine, and
methotrexate [68, 71, 72]. Data from the French AutoImmu-
nity and Rituximab registry (n = 136) on RTX-treated patients
with SLE showed 71% overall response rate by the SELENA-
SLEDAI assessment; articular, mucocutaneous, renal, and
hematologic improvements were noted in 72%, 70%, 74%,
and 88% of patients, respectively. Interestingly, the efficacy of
RTX monotherapy was not significantly different from that of
RTX in combination with immunosuppressants [66].
In another clinical trial performed in the pediatric popu-
lation, the RTX regimen without long-term oral CS showed
efficacy in patients with LN [72]. Two doses of RTX (1 g/dose
at 14-day intervals) and 2 IV methylprednisolone pulses (500
mg on days 1 and 15) were given to patients (n = 50) in
combination with MMF maintenance therapy. A total and
partial response at week 52 was obtained in 52% and 34% of
participants, respectively. On the basis of promising results
of the described therapeutic regimen, a similar clinical trial
was commenced aiming to compare the regimen above with
a conventional oral prednisone dose of 0.5 mg/kg BW/day
in combination with MMF, but without RTX (RITUXILUP
study) [73].
A substantial variability of B cell depletion rate follow-
ing anti-CD20 therapy is described, which may influence
the response and the frequency of SLE flares during RTX
treatment. The phenomenon of poorer response to the drug
concerns in particular those patients who exhibit more
rapid repopulation of memory B cells and plasmablasts [74].
Increased baseline BLyS level and development of RTX-
neutralizing antibodies are associated with worse clinical
response [75, 76]. Due to the frequently observed increase
in BLyS level after RTX treatment of potential clinical
relevance, a proof-of-concept study was initiated to evaluate
the sequential administration of belimumab after induction
therapy with CY combined with RTX in patients with LN
(CALIBRATE) [77, 78]. A clinical trial aimed at assessing
the efficacy of belimumab in combination with RTX began
recruitment in early 2018 [79].
RTX, as a chimeric antibody, can cause hypersensitivity
reactions which have been reported in 10-15% of patients with
SLE [80]. Another significant issue in the treatment of SLE
patients with RTX seems to be a relatively high frequency of
8 BioMed Research International
so-called human antichimeric antibodies (HACAs). The clin-
ical relevance of HACA formation in RTX-treated patients is
not yet fully elucidated [76].
(2) Ocrelizumab. Ocrelizumab is a fully humanized (90%)
anti-CD20 monoclonal antibody synthesized to reduce
immunogenicity and increase tolerability [81]. Ocrelizumab
is the first disease-modifying treatment registered for patients
with early primary progressive multiple sclerosis [82]. In
vitro studies of this molecule have demonstrated increased
antibody-dependent cell-mediated cytotoxicity and lower
complement-dependent cytotoxicity compared to RTX [83].
Two phase III clinical trials evaluating this agent in patients
with SLE have been completed; the first study examined the
efficacy of ocrelizumab in SLE without renal involvement
(BEGIN), while the second one recruited patients with LN
(BELONG). The BEGIN study was terminated prematurely
due to the lack of response.
In BELONG trial, patients with active proliferative LN
received ocrelizumab or placebo on the background of either
MMF or CY in the so-called Euro-Lupus regimen (500 mg IV
CY every 2 weeks to a total of 6 doses and azathioprine). The
trial was also terminated early due to a significant increase
in serious infections (in the MMF + ocrelizumab group).
The efficacy analysis showed a nonstatistically significant
numerical superiority of ocrelizumab over placebo; complete
renal response in the ocrelizumab treatment groups (67%)
was achieved nonstatistically more frequently than in the
placebo group (55%). The response rate was higher in patients
receiving ocrelizumab with CY than in those on ocrelizumab
with MMF. Severe infections were statistically more frequent
within the MMF group [84, 85].
(3) Ofatumumab. Ofatumumab is a fully human IgG1𝜅
monoclonal antibody that binds to a unique epitope on the
human CD20 molecule expressed on the surface of B cells;
this agent has low immunogenicity [86]. Ofatumumab was
often used off-label to treat SLE, in particular in responders
to RTX who developed hypersensitivity to this drug [87–89].
In clinical trials conducted in chronic lymphocytic leukemia
and rheumatoid arthritis populations, no significant induc-
tion of anti-drug antibodies was observed [90, 91]. Formal
clinical trials on the use of this drug in SLE are expected.
(4) Obinutuzumab. Obinutuzumab is a novel fully humanized
glycoengineered IgG1 type II monoclonal antibody against
CD20, which is used in the treatment of patients with chronic
lymphocytic leukemia [92]. In vitro study showed its greater
capacity for B cell depletion compared to RTX [93]. A 52-
week phase II trial in patients with LN is ongoing with
complete renal response as a primary end point [94].
2.4. Anti-CD22 Monoclonal Antibodies
2.4.1. Epratuzumab. Epratuzumab is a recombinant, human-
ized IgG1 monoclonal antibody directed selectively against
the CD22 antigen on the surface of mature B cells; CD22 is
a B cell-specific surface antigen involved in the modulation
of BCR signaling, cellular activation, and B cell survival
[95]. Epratuzumab and RTX display distinct modes of action;
epratuzumab acts as an immunomodulatory nondepleting
agent, while RTX is an acutely cytotoxic molecule [96].
In vitro, epratuzumab has been shown to rapidly induce
a significant reduction of CD22, CD19, CD21, and CD79b
on the surface of B cells in both Fc-dependent and Fc-
independent mechanisms. The functional consequence of
binding epratuzumab to CD22 is inhibition of B cell prolifer-
ation and reduced expression of adhesion molecules and the
synthesis of proinflammatory cytokines, such as interleukin
6 (IL-6) and TNF-𝛼 [97]. Epratuzumab is unable to induce
complement-dependent cellular cytotoxicity; therefore it is
safer than RTX with no infusion reactions reported so far.
In clinical studies, epratuzumab led to a modest reduction
in peripheral B cells without significant effect on T cells,
autoantibody titres, and Ig levels after prolonged therapy [98–
100].
EMBLEM was a phase IIb double-blind, randomized,
placebo-controlled trial evaluating epratuzumab in patients
with moderate-to-severe SLE (no severe neuropsychiatric
SLE and LN patients were included in the study) [100].
At week 12, the overall proportion of responders was
insignificantly higher in all groups of patients treated with
epratuzumab. The frequency of AEs and serious AEs (includ-
ing infusion reactions) was comparable in all patient groups.
The study was later extended to an open-label phase for
a follow-up period of 3.2 years which showed sustained
improvements in disease activity and QoL. Serious infections
developed in 6.9% of those treated; however the average dose
reduction of CS was 50% at week 108 [101].
Subsequently, two phase III randomized, double-blind
clinical trials with epratuzumab (EMBODY 1 and EMBODY
2) were performed, which recruited patients with moderate-
to-severe seropositive SLE (≥6 points in SLEDAI-2K and ≥1
A domain and ≥2 in the mucocutaneous, musculoskeletal, or
cardiorespiratory domains in BILAG 2004) despite the use of
standard therapy, including mandatory treatment with CS.
Patients with BILAG A in the renal and neuropsychiatric
domains were not included in this study. Patients received
either epratuzumab in one of two dosing schemes (600 mg
every week or 1,200 mg every other week) or placebo. All
patients maintained their previous background SLE thera-
pies. The primary end point was the degree of response based
on BICLA (BILAG-based Combined Lupus Assessment),
a composite index based on BILAG. The study included
a large number of patients (n = 1574); unfortunately, no
statistically significant difference in end points (both primary
and secondary) between the groups receiving the drug and
placebo was found. The frequency of AEs was similar across
all study arms. Neither the primary outcome nor any of the
secondary outcomes were achieved in the aforementioned
trials; therefore epratuzumab is no longer being developed for
SLE [102].
3. Type I Interferon-Targeted Therapies
Activation of type I interferon (IFN) system is considered
to be a key player in SLE immunopathogenesis [103–105].
Cell signalling of all type I IFNs, i.e., IFN𝛼, IFN𝛽, IFN𝜀,
BioMed Research International
IFN𝜅, and IFN𝜔, is mediated by the so-called IFNAR (type
I IFN-𝛼/𝛽/𝜔 receptor), resulting in IFN-stimulated gene
transcription, also referred to as IFN gene signature [106]. It
is therefore believed that IFNAR blockade may reverse some
of the immunological imbalance developed by SLE patients
[107].
IFN𝛼 is produced by many cell types, yet its synthesis by
plasmacytoid DCs in particular is of the greatest importance
from the point of view of the pathogenesis of SLE. In SLE,
production of type I IFNs by plasmacytoid DCs is induced by
complexes consisting of DNA/RNA-containing autoantigens
through Fc𝛾R-dependent internalization of these complexes
and activation of the toll-like receptor 7 (TLR-7) and TLR-
9 [108]. IFN𝛼 promotes DC formation, activation of T cells,
and production of autoantibodies by B cells [109]. Elevated
levels of IFN𝛼 and IFN-dependent cytokines, as well as
expression of IFN-regulated genes, correlated with serologic
disease activity markers, such as anti-dsDNA antibodies,
complement components, and IL-10 levels [110–116]. In addi-
tion, polymorphisms of many components of IFN-dependent
signaling pathways were shown to be associated with higher
susceptibility to SLE [117].
3.1. Rontalizumab. Rontalizumab is a human monoclonal
IgG1 antibody that neutralizes all known IFN𝛼 subtypes but
does not bind to IFN𝛽 or IFN𝜔. A phase I clinical trial
established the safety and efficacy of the molecule in reducing
the expression of IFN-regulating genes [118]. Immediately
thereafter, a phase II clinical trial was conducted on a group
of 238 patients with moderate-to-severe SLE (defined as
BILAG A in ≥1 domain or BILAG B in ≥2 domains) and
no renal involvement. Prior to its initiation, all background
therapy was discontinued except for hydroxychloroquine,
and the dose of prednisone (or equivalent) was tapered to
≤10 mg/day by week 8. At week 24, no significant difference
in treatment response was seen based on BILAG and SRI
between patients treated and those receiving placebo. The
drug was well tolerated and no significant increase in the
frequency of infections was observed [119]. Disappointingly,
due to a lack of efficacy, further work on this molecule has
been stopped.
3.2. Sifalimumab. Sifalimumab is a fully humanized IgG1𝜅
monoclonal antibody that has the ability to bind and neutral-
ize most of the 13 known IFN𝛼 subtypes. Two phase I clinical
trials demonstrated the safety of this molecule in patients
with seropositive SLE with moderate-to-high activity [120,
121]. Post hoc analysis of the efficacy showed that the clinical
effectiveness of the drug was better in patients with high
initial expression of IFN gene signatures. Phase II clinical
trial was conducted on a relatively large group of patients
(n = 431) with active SLE (SLEDAI ≥6 points, BILAG A in
≥1 domain, and BILAG B in ≥2 domains, PGA ≥1); patients
with CNS involvement were not included in the study. At
week 52 a better response (measured by the percentage of
SRI-4 improvement) was observed in the groups treated with
all 3 doses of sifalimumab (200/600/1,200 mg) than in the
placebo group (59.8% vs. 45.4%; p = 0.03). There was also
9
a skin score improvement expressed in the reduction in
CLASI (Cutaneous Lupus Erythematosus Disease Area and
Severity Index) and a reduction in tender and swollen joint
counts. Similarly to the observations from the previous study,
patients with high baseline IFN gene signatures responded
better. Sifalimumab was safe and well tolerated [122]. Inter-
estingly, this drug did not affect immunological parameters
of SLE activity, such as the concentration of anti-dsDNA
antibodies and C3/C4 complement component titers in the
serum. Despite confirming that blockade of type I IFNs is an
effective measure to treat SLE and demonstrating the clinical
efficacy of sifalimumab, the sponsor did not continue the
development of this molecule.
3.3. Anifrolumab. Anifrolumab is a fully human IgG1𝜅 mon-
oclonal antibody that binds to IFNAR I by inhibiting the
activity of all type I IFNs, including IFN𝛼, IFN𝛽, IFN𝜀, IFN𝜅,
and IFN𝜔 [123, 124]. Phase I clinical trial showed a greater
and more prolonged suppression of IFN gene signatures in
patients with SLE receiving anifrolumab compared to those
using sifalimumab [125]. A subsequent 48-week phase IIb
clinical trial was conducted with a double-blind, randomized,
and placebo-controlled study in patients with nonrenal SLE
who were not responding adequately to standard treatments.
Participants were randomized to one of two groups receiving
anifrolumab IV at different doses (300 mg or 1,000 mg) or
to a placebo group. The primary end point was to achieve
an SRI-4 response and maintain the prednisone dose at 10
mg/day or lower by day 169; it was met by a significantly
larger proportion of patients treated with 300 mg of anifrol-
umab than by placebo receivers (34.3% vs. 17.6%; p = 0.01,
respectively). As expected, improvement in relation to the
achievement of the primary end point as well as secondary
end points (improvement of cutaneous manifestations, CS-
sparing effect) was more strongly expressed in patients with
high IFN gene expression. The drug was well tolerated [126].
Encouraging results of the above described clinical trial
enabled the planning of further phase II and III trials for
patients with SLE and LN [127–130].
4. Cytokine Targeting Treatments
4.1. Tumor Necrosis Factor-Alpha (TNF-𝛼) Inhibitors. The
role TNF-𝛼 plays in SLE pathogenesis remains controversial.
On the one hand, the level of this cytokine is elevated
in serum and renal biopsy samples of patients with active
disease; on the other hand, it is possible to induce antinuclear
antibodies, and even full-blown SLE, with TNF-𝛼 antagonists
[131, 132]. The results of a pilot clinical trial evaluating inflix-
imab in SLE conducted on a small group of patients suggested
that anti-TNF-𝛼 antibodies could be used in the treatment
of LN, as well as refractory lupus arthritis and cutaneous
manifestations of the disease. However, the appearance of
antinuclear, anti-dsDNA, and anti-phospholipid antibodies
was observed in rheumatoid arthritis patients [133, 134]. In
view of the above, TNF-𝛼 blocking molecules are currently
not recommended for the treatment of SLE and confined to
heavily refractory cases only.
10
4.2. Interleukin-6 Inhibitors
4.2.1. Tocilizumab. Tocilizumab is a humanized IgG1 mono-
clonal antibody directed against both soluble and membrane-
bound IL-6 receptors [135]. IL-6 is a proinflammatory
cytokine involved in the differentiation of B cells into plasma
cells and T cells into effector T cells. IL-6, secreted mainly
by macrophages and T cells, acts synergistically with type I
IFN [136]. It is suggested that IL-6 may be the key driver of
B cell hyperactivity in SLE and may mediate tissue damage
in the course of the disease [137]. The increased levels of
this cytokine in serum, renal, and skin biopsy samples in
patients with SLE positively correlated with disease activity
and serum anti-dsDNA antibodies titers [138, 139]. In a
phase I clinical trial that assessed the efficacy of tocilizumab
in SLE, there was a significant improvement in clinical
parameters, in particular in the joints, as well as in serum anti-
dsDNA antibodies. The incidence of AEs, primarily dose-
dependent neutropenia and mild-to-moderate infections, did
not significantly differ from those documented in rheumatoid
arthritis trials [140].
4.2.2. Sirukumab. Sirukumab is another IL-6 blocking mon-
oclonal antibody that binds directly to this cytokine. In
phase I, placebo-controlled trial in patients with SLE or
cutaneous LE the administration of sirukumab led to a
dose-independent reduction in the number of leukocytes,
neutrophils, and platelets. Treatment was well tolerated;
infections and other AEs were only slightly more frequent
than in the placebo group [141]. Subsequent phase II proof-
of-concept study was conducted in which patients were
randomized to receive IV administration of sirukumab (10
mg/kg BW every 4 weeks until week 24) or placebo. The study
was carried out on a group of 25 patients with International
Society of Nephrology/Renal Pathology Society (ISN/RPS)
class III/IV LN and persistent proteinuria despite standard-
of-care treatment. Sadly, this trial did not show the expected
safety and efficacy of the drug; as many as 48% of the treated
patients experienced AEs, mostly infections [142].
5. Interleukin-2
IL-2 plays a key role in the activation and stimulation of T
cell proliferation [143, 144]. The reduced production of IL-2
in patients with SLE is most likely the underlying cause of
pathogenically significant abnormalities, including reduction
of counterinflammatory regulatory T cell subset counts and
the number of cytotoxic lymphocytes [145]. In a clinical trial
performed on a small group of patients with SLE (n = 38)
who received low-dose IL-2, almost 90% SRI-4 response rate
was demonstrated. In addition, a decrease in the serum levels
biomarkers for SLE (complement components, anti-dsDNA
antibodies) and proteinuria was observed [146]. However,
this promising result needs to be confirmed in a placebo-
controlled, blinded study.
6. Complement-Targeted Therapies
Early complement components are an important element
of immune complexes and apoptotic cells clearance systems
BioMed Research International
in SLE patients. These proteins play an important role in
regulating the function of both T and B cells. Terminal
complement components activation is associated with flares
of the disease and directly responsible for tissue and organ
damage, particularly in the course of LN [147].
6.1. Eculizumab. Eculizumab is a humanized monoclonal
antibody that binds to the C5 complement protein, which
prevents its degradation into the active forms of C5a and
C5b and the formation of the C5b-9 complex (the alter-
native pathway for complement activation). This molecule
therefore protects against the consumption of early com-
plement components (C1-C4). Eculizumab is registered for
the treatment of paroxysmal nocturnal hemoglobinuria and
the atypical form of hemolytic-uremic syndrome [148]. In
view of promising observations from experimental studies
on mouse lupus models, phase I study with a single dose
of the drug was undertaken; eculizumab was safe and well
tolerated. Notably, the effectiveness of complement blockade
was noted for higher doses alone and only in the first 5-10 days
of treatment; no improvement in the final stage of the study
was observed [149].
7. T Cell Costimulation Blockade
7.1. Anti-CD40L Antibodies
7.1.1. Ruplizumab and Toralizumab. Ruplizumab is a human-
ized monoclonal antibody directed against the CD40 ligand
(CD40L, CD154) preventing the activation of T cells and
the dependent activation of B cells [150]. A clinical trial
was conducted with this molecule in LN, which was pre-
maturely terminated due to thromboembolic complications.
This serious AE was attributed to the binding of the drug
Fc receptor to the platelet IgG Fc IIA receptor (Fc𝛾RIIA)
[151]. Preliminary analysis of the treatment results showed
a marked decrease of hematuria and proteinuria, as well as
the serum level of complement components and anti-dsDNA
antibody titres. Administration of toralizumab, a molecule
with a similar mechanism of action, was also associated with
thromboembolic complications that prevented its further use
[152].
7.1.2. Dapirolizumab. Dapirolizumab (known as anti-CD40L
Fab-PEG) is a new anti-CD40L antibody that contains a
PEGylated Fab’ fragment with no Fc portion. For this reason,
it is considered safer than its predecessors described above.
Phase I clinical trial, lasting 32 weeks, showed a decrease in
disease activity in the treatment group. No significant AEs
were observed, including thromboembolic complications
[153]. It needs to be pointed out that, due to the small number
of recruited patients, further evaluation of this improved
biologic is required to properly address its efficacy and safety.
Recruitment for the phase II trial is in progress [154].
7.2. Inhibition of the CD28:CD80/CD86 T Cell
Costimulatory Pathway
7.2.1. Abatacept. Abatacept (CTLA4Ig) is a recombinant sol-
uble fusion protein composed of the extracellular domain
BioMed Research International
of the human cytotoxic T-lymphocyte-associated antigen 4
(CTLA-4) and a modified Fc fragment of human Ig 1 (IgG1).
Abatacept selectively modulates a key costimulatory signal
that is necessary for the full activation of CD28+ T cells.
Abatacept has the ability to bind and block CD80 (B7-1) or
CD86 (B7-2) molecules on the surface of antigen presenting
cells with greater affinity than CD28, inhibiting this key cos-
timulatory signaling pathway for T cell activation. Abatacept
inhibits mainly naı̈ve T cell activation and has a much less
pronounced effect on inhibiting the activation of memory
CD4+ T cells [155]. Studies on mouse models of SLE showed
that abatacept delayed the development of autoimmunity and
decreased mortality by reducing the number of autoreactive B
cells, diminishing Ig class switching and antibody production,
as well as reducing the severity of LN [156, 157]. Abatacept
and CY combination had a greater effect on disease severity
reduction and mortality than any of these drugs used alone
in NZB/W mice with LN [158].
In a randomized, double-blind, placebo-controlled phase
IIb trial, patients with non-life-threatening SLE whose pri-
mary manifestations were active polyarthritis, discoid lupus
erythematosus skin lesions, and serositis (pleuritis and/or
pericarditis) were receiving abatacept in combination with 30
mg/day prednisone with subsequent tapering 1 month into
the therapy. After 12 months of treatment, there were no
significant differences in the percentage of patients achieving
a primary and secondary end point between the abatacept
and placebo groups. However, it was observed that patients
with polyarthritis as the main manifestation of the disease
achieved the greatest benefits from the therapy. Serious AEs
were more frequent in the actively treated group [159].
Another multicentre, randomized, double-blind phase
II/III clinical trial that aimed to evaluate the efficacy of the
drug was conducted in patients with active LN (ISN/RPS class
III/IV). Abatacept was administered in two dosing regimens
in combination with prednisone and MMF. At week 52,
the composite primary end point, i.e., the time required to
achieve complete renal response (urine protein/creatinine
ratio <0.26, inactive urinary sediment, and glomerular filtra-
tion rate decline not greater than 10% compared to baseline),
did not differ significantly between the treatment groups and
the placebo group [160].
The previously described efficacy of combined adminis-
tration of abatacept and CY was the driving force behind the
randomized, double-blind, placebo-controlled phase II add-
on clinical trial (ACCESS), which enrolled 134 patients with
LN. Patients were treated with either abatacept or placebo
in conjunction with the Euro-Lupus regimen of low-dose
CY followed by azathioprine [161]. At week 24, no statisti-
cally significant difference was found in the complete renal
response between the abatacept and placebo group (33% vs.
31%). Significant benefits in patients receiving abatacept have
also not been observed with respect to partial renal responses
or other secondary end points, i.e., reduction of anti-dsDNA
antibody levels, normalization of serum concentration of C3
and C4 complement components, shortening of the time
needed to achieve complete/partial renal response, improve-
ment of QoL, and frequency of SLE flares. About a half
of abatacept-treated patients who achieved complete renal
11
response and, according to the study protocol, discontinued
the additional administration of immunosuppressive drugs at
week 24 maintained this response by week 52. Treatment was
well tolerated [162].
A Phase III, randomized, double-blind, placebo-
controlled clinical trial is underway to assess the safety and
efficacy of abatacept in patients with active ISN/RPS class
III/IV LN treated with MMF and prednisone simultaneously
[163].
8. Summary
The results of the clinical trials conducted so far with bio-
logical drugs in SLE are not encouraging. The only molecule
whose use in extrarenal disease is fully justified is belimumab
with its modest effect on lupus activity. Despite the promising
results of SLE therapy using RTX in cohort observations
and numerous reports on the advantages of including this
monoclonal antibody in standard therapy, the results of
two major clinical trials (EXPLORER and LUNAR) were
contrasting with the perceived “real-life” benefits. To the best
of the current knowledge, the remaining biotherapies can at
most be used in narrow, currently not yet fully identified
subsets of patients in terms of clinical and immunological
features.
SLE is a disease with a serious prognosis that runs an
unpredictable, often life-threatening, course. With these fea-
tures of lupus in mind, the recruitment of patients with a high
severity of disease symptoms due to risk of significant disease
progression in the control group or in case of inefficacy
of the studied molecule in the treated group is difficult to
estimate. Usually, recruitment of patients with fairly low
disease activity and/or a less aggressive course is preferred,
with the exception of those clinical trials focusing on LN.
A very high clinical heterogeneity of SLE poses major
difficulty at the level of design and implementation of
clinical trials. The complex nature of SLE makes it thus
almost unrealistic to recruit a homogeneous subpopulation
of patients. A potentially meaningful solution for overcoming
this tendency that could be employed is designing more
clinical trials or subtrials with an organ-specific approach
instead of disease activity-specific strategy of recruitment. It
would allow obtaining more homogenous population for a
trial; however, enrollment of adequate number of patients
would be more challenging.
The lack of consistency between the various tools utilized
to assess disease activity and different composite indices
employed as the primary end points generate discrepancies
in the evaluation of patients, hindering the final analysis
and interpretation of the clinical trial results. For instance,
numerous examples have been provided that the treatment
efficacy of patients with LN, a seemingly homogeneous sub-
population, evaluated using different tools led to markedly
divergent results [164]. Comprehensive evaluation of the
patient, forced by the complex nature of SLE, is not always
possible to perform accurately in the clinical trial setting.
In addition to constant attempts to develop new
molecules, works on identifying new targets for SLE therapy
are equally intense [165]. Despite the above described
12
failures, there has been a significant increase in the number
of clinical trials conducted using innovative methods of
treatment in patients with SLE in recent years. It remains to
be hoped that the extremely dynamic development of basic
research and the breakthrough in biological therapy of other
autoimmune diseases will finally allow an effective and safe
long-term control of SLE in the near future.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
This manuscript has been prepared without third-party
contribution nor financial support.
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